PROJECT SUMMARY/ABSTRACT Keratoconus (KC) is the most common corneal dystrophy, with adverse corneal changes that can dramatically affect vision. During KC progression, the cornea can show several pathologies, including fragmentation of Bowman?s layer, thinning of stroma and overlying epithelium, folds or breaks in Descemet?s membrane, and variable amounts of diffuse corneal scarring. Clinically, limited treatment options for KC patients include corneal transplantation and collagen cross-linking. Unfortunately, both corneal transplantation and collagen cross-linking have their own limitations. To date, the etiology and pathogenesis of KC remains unclear. As such, there is an urgent need to identify viable biomarker(s) that can help with the early diagnosis and treatment of KC. In 2014, we were the first to report the role and significant modulation of prolactin-induced protein (PIP) in vitro (3D cultures with human KC cells) and in vivo (human tear samples), and question its role during KC development and progression. Our preliminary data shows that PIP is significantly downregulated in KC patients when compared to Healthy individuals. Interestingly, downregulation of PIP was seen in three different human biological fluids: saliva, tears, and blood (serum). Furthermore, our preliminary data shows that PIP is not modulated in other relevant diseases, such as Uveitis and Type II Diabetes, suggesting potential specificity to KC. Even more strikingly, new data shows that PIP expression levels returned to normal on KC patients that had received corneal transplants. We posit that PIP can serve as a biomarker for KC onset and progression drive the development of future non-invasive treatment modalities. The current proposal is focused solely on PIP, with three main goals: 1) Cement PIP as a KC biomarker, 2) Determine the power and specificity of PIP, and 3) Determine PIP expression following known KC treatments. To ensure that we achieve our goals, we have assembled a large cohort of experts in the field from multiple clinical and research centers, as well as from the National Keratoconus Foundation (NKCF). Successful completion of the studies proposed will be a breakthrough in KC research and will alter current standards of care for patients with KC. Relevance to Public Health ? KC is a major clinical problem resulting in visual impairment worldwide. There is an urgent need to develop novel diagnostic tools for the detection and treatment of KC in the early stages. Ultimately, the primary goal is to enable people with KC to live a normal life with little or no visual disability. The proposed work will move the field forward, is translational, clinically relevant, and in line with NEI?s program goals: ?Apply the knowledge acquired from discoveries in the basic science of the cornea and other tissues of the ocular surface to the diagnosis, prevention, and treatment of ocular injury and disease?.